Figure 2. Post-transcriptional regulation of stem cell identity under conditions of stress.

In response to proteotoxic insults, the cell mounts adaptive responses to maintain protein quality control. These stress response pathways also regulate stem cells. (A) The heat shock response induces ESC differentiation, protects ESCs from cellular stress, promotes myoblast differentiation, and supports erythropoiesis. (B) Activation of the UPR^MT by nicotinamide riboside delays neural stem cell and melanocyte stem cell senescence, while dysregulation of the UPR^MT also impairs hematopoietic and intestinal stem cell stemness and proliferation. (C) Post-transcriptional mechanisms of gene regulation including RNA methylation and protein synthesis can regulate the cellular response to oxidative stress. However, the precise nature of this relationship and its influence on stem cells is largely unknown. (D) The effects of UPR^ER activation on stem cells are tissue- and context-specific. Activation of the PERK branch regulates muscle satellite cell differentiation during homeostasis, but results in a loss of intestinal stem cell self-renewal during stress. Induction of ATF6 and IRE1 through pharmacological means supports mesodermal specification of ESCs and enhances the reprogramming efficiency of somatic stem cells. Activation of the PERK branch during homeostasis promotes the engraftment of HSCs, and during conditions of moderate stress promotes their survival. The IRE1 pathway provides a protective effect on HSCs experiencing stress. However, extreme stress induces HSC apoptosis.